The purpose of this grant is to support a surgical metabolic laboratory for the study of certain parameters of cholesterol, bile acid, and lipoprotein dynamics and kinetics. Three surgical procedures -- partial ileal bypass, jejuno-ileal bypass and portacaval shunt -- are metabolic tools to obtain such data. Partial ileal bypass physiology and biochemistry represent the primary concern of our research group for the past 14 years. Proposed future studies in this area include: acquisition of clinical program data; animal cholesterol dynamics (absorption, excretion, synthesis, turnover and pool sizes) studies, including investigation of a blood-borne physiologic cholesterol synthesis inhibitor; animal atherosclerosis implications; human cholesterol and bile acid dynamics studies of the lithogenicity of bile, specific bile acid patterns, bile acid turnover and pool sizes, plasma bile acid levels, and lipoprotein kinetics before and after partial ileal bypass; analysis of the effect of intestinal bypass surgery on gastric secretion and gastrin levels; and rheological studies of red blood cell membrane and plasma oxygen permeability, viscosity and cellular deformability in hyperlipidemia. The second area of our proposed research concerns the jejuno-ileal operation for obesity and includes the acquisition of clinical data; study of cholesterol dynamics and lipoprotein kinetics; study of the effect of this bypass on the lithogenicity of bile; study of bile acid patterns, dynamics, and plasma levels in obese patients before and after jejuno-ileal bypass; and development of a genetic obese animal model to study the metabolic consequences of jejuno-ileal bypass surgery. Finally, the third major area of exploration involves analysis of lipid mechanisms associated with the portacaval shunt, including a study of the possible synergistic effect of portacaval shunt and partial ileal bypass.